HSF1 Activation Mechanisms, Disease Roles, and Small Molecule Therapeutics

The heat shock factor 1 (HSF1) is a master transcription regulator that orchestrates the expression of heat shock proteins (HSPs) in response to various cellular stresses. Dysfunction of HSF1 contributes to the pathogenesis of a spectrum of acute and chronic diseases, including cancer. Consequently, the modulation of HSF1 activity through the development of small molecules emerges as a promising therapeutic strategy for disease treatment. The activation of HSF1 is a multifaceted process, governed by a complex interplay of regulatory mechanisms, including post-translational modifications, protein-protein interactions, and a balance between its activation and inactivation. Recently, a plethora of compounds, ranging from synthetic to naturally derived, that either inhibit or activate HSF1 was identified, holding considerable potential for the treatment of numerous human diseases. In this comprehensive review, we elucidate the sophisticated mechanisms underlying activation of human HSF1, introduce its role in the etiology of diseases, and provide a comprehensive summary of the inhibitors and activators of HSF1 that have been discovered to date. This review not only offers novel insights for the development of small molecule therapeutics targeting HSF1 but also charts new territories in the design of innovative interventions for the amelioration of disease.